1. Field of the Invention
This invention relates to a pharmaceutical composition comprising a 1:1 solvate of 5-(5,5-dimethyl-1,3,2-dioxaphosphorinane-2-yl)-1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl)-3-pyridine carboxylic acid 2-(phenyl(phenylmethyl)amino) ethyl ester P-oxide hydrochlorideethanol (such a solvate is herein abbreviated as "NZ-105") possessing hypotensive activity.
2. Description of the Background
The effective pharmaceutical component, NZ-105, of the composition of this invention is a derivative of 1,4-dihydropyridine-5-phosphonic acid and has the following chemical formula: ##STR1## wherein Ph represents a phenyl group. This is a novel compound possessing vasodilative and hypotensive activity on account of its calcium antagonistic activity and useful as a cardiovascular drug.
Nicardipine and nifedipine are well known as 1,4-dihydropyridine-type compounds. Because of very poor solubility in water, these compounds can not be absorbed through gastrointestinal tracts in a sufficient amount. Improvement in the solubility of these compounds has thus been desired in view of the promotion of their bioavailability. Various methods have been proposed to improve solubility of these compounds, including dissolving these compounds into an organic solvent, pulverizing the compounds, utilizing multi-crystal forms, formulating a surface active agent or a polymeric compound, etc. Japanese Patent Publication No. 48810/1984, for example, proposes converting nicardipine hydrochloride into an amorphous type. Japanese Patent Laid-open No. 123117/1987 discloses formulating an organic acid and a water soluble polymer to nicardipine hydrochloride to promote its solubility. Methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, or a mixture of these compounds are used as water soluble polymeric compounds. Other polymeric compounds are polyvinylpyrrolidone, methacrylic acid-methylacrylate copolymer, carboxymethylethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose phthalate acetate, and the like.
Based on this technological background, the present inventors have studied the possibility of promoting the bioavailability of NZ-105 by pulverizing its crystals. This method, however, did not result in an improvement in the solubility of NZ-105 of a degree to promote its bioavailability.
Formulating a polymeric compound to NZ-105 was also studied. None of the above-mentioned polymers which have been proposed for use in conjunction with 1,4-dihydropyridine-type compounds gave a satisfactory improvement in the promotion of the solubility of NZ-105. Besides, the formulation of such a polymer as polyvinylpyrrolidone, hydroxypropylcellulose, or hydroxypropylmethylcellulose into a preparation of NZ-105 required the use of a larger amount of a disintegrator in the tablet to ensure disintegration of the tablet in digestive organs resisting the binding force of these polymeric compounds. This entailed larger size tablets. Other polymeric compounds, such as hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, methacrylic acid-methylmethacrylate copolymer, polyvinylacetaldiethylaminoacetate, and the like, required the use of a relatively large amount of these compounds to be formulated in order to improve the solubility of NZ-105 and to promote its bioavailability. This also entailed larger size tablets.
A need has therefore existed for a stable composition of an NZ-105 preparation possessing a sufficient bioavailability and easily prepared into tablets, capsules, granules, powders, etc.
The present inventors have conducted further studies in order to resolve the above-mentioned problems and found that by formulating hydroxypropylmethylcellulose acetate succinate (hereinafter abbreviated as "HPMCAS") into NZ-105 a composition having a remarkably enhanced bioavailability and easily prepared into tablets, capsules, granules, powders, and the like could be obtained. Such a finding has led to the completion of the present invention.